The present invention relates to monoclonal antibodies capable of reacting with shared idiotypes on human anti-native DNA antibodies. The invention also relates to diagnostic test methods to detect the presence of anti-native DNA antibodies in patients suspected of having systemic lupus erythematosus.
The term "antibody" as used in immunology is a generic term and is used to cover numerous immunoglobulin molecules which may be alike in some respects and different in other respects. Antibodies sharing a common effector function are referred to as isotypes and include the major immunoglobulin classes IgA, IgD, IgE, IgG and IgM, each of which is constructed from a heavy polypeptide chain characteristic of the particular class and a light polypeptide chain (either kappa or lambda), the heavy and light chains being joined by disulfide bridges. Heterologous antibodies, i.e. those raised in one species against the antibodies of another species, are useful in recognizing isotypes.
Antibodies of a given isotype, e.g., IgG, can be subdivided further on the basis of the particular type of heavy chain from which they are composed, e.g. .gamma.1, .gamma.2, .gamma.3, etc. Antibodies having the same general type of heavy chain can still show some heterogeneity in the heavy chain. Within a given animal species, certain regions on the heavy chain of a given isotype may be the same or different. Those antibodies showing similarity within these regions are referred to as allotypes. The similarity is believed to be of genetic origin.
Finally, antibodies of a given isotype and allotype may differ on the basis of their structure in or near their antigen binding regions (Fab region). Antibodies showing similarity in this region are said to be of the same idiotype. Particular discrete antigenic sites within these regions are referred to as idiotypic determinants or frequently just idiotypes. Antibodies having common or shared idiotypes generally have the same antigenic specificity.
Despite common antigenic specificity among idiotypes, not all idiotypic determinants are located in the antigen binding site of an immunoglobulin molecule. This has been demonstrated by the fact that a second antibody directed against an idiotypic determinant on the first antibody (the second antibody being referred to hereinafter as an anti-idiotypic antibody) and the antigen do not always compete for the antigen binding site on the first antibody. Idiotypic determinants are controlled by both genetic and antigenic influences. Antibodies from genetically different individuals which share a common antigenic specificity usually exhibit idiotypic heterogeneity. That is, even though the antibodies are capable of binding the same antigen, the structure of idiotypic determinants, even when located in the antigen binding site, are different.
Antibodies directed against idiotypic determinants on immunoglobulin molecules provide unique probes for detecting antibodies associated with and characteristic of auto-immune diseases. Serum containing anti-idiotypic antibodies has been used to demonstrate shared idiotypes on immunoglobulins from unrelated patients in a number of auto-immune diseases including myasthenia gravis, Graves Disease, cold agglutinin disease, and rheumatoid arthritis. Antibodies to native DNA (anti-nDNA) produced by inbred mice with diseases resembling human systemic lupus erythematosus (SLE) have been shown to share a common idiotype, but shared idiotypy has not previously been demonstrated in the anti-nDNA antibodies of human patients with SLE.
Systemic lupus erythematosus is a disease which is being diagnosed with ever-increasing frequency. A minimal estimate of its incidence is 10 per 100,000 people, but it occurs preferentially in blacks and in women of child-bearing age. Its incidence in family members of patients with SLE is at least one hundred fold greater than its incidence in the population at large, but the genetics of inheritance remain unclear. Systemic lupus erythematosus is a disease of protean manifestations both clinically and serologically. Clinically, SLE can affect any organ system. it causes constitutional systems such as fever and malaise. It causes arthritis, serositis (plural, peritoneal, and pericardial), renal disease, hematologic abnormalities, and central nervous system disturbances. The sera from lupus patients are capable of reacting with a variety of antigens due to the presence of auto-antibodies. These antibodies are directed primarily against nuclear antigens and cell membrane antigens, although some antibodies to cytoplasmic antigens have been described. The auto antibody which is specific for SLE and most commonly found in the serum from SLE patients is antibody to native DNA.
As stated earlier, one individual generally produces many different antibodies against a given antigen such as DNA. While all such antibodies are capable of reacting with the common antigen, the antibodies may exhibit structural differences, thereby imparting idiotypic heterogeneity. Furthermore, additional idiotypic difference will generally exist between antibodies produced by genetically nonidentical individuals against a common antigen. Consequently, one would expect that in the genetically diverse human population, there would be wide heterogeneity in anti-DNA antibodies from patients with SLE. Therefore, an anti-idiotypic antibody produced against an anti-DNA antibody from one individual would not be expected to cross react with anti-DNA antibodies from other genetically nonidentical individuals within the population. In the present invention, monoclonal anti-idiotypic antibodies have been produced against the anti-native DNA antibodies from one SLE patient which, unexpectedly, do cross react with anti-nDNA antibodies from genetically nonidentical SLE patients within the human population. This unexpected cross-reactivity allows these monoclonal antibodies to be used as diagnostic reagents to detect anti-nDNA antibody in serum from suspected SLE patients within the population at large.